KRAS status and risk of venous thromboembolic events in patients with metastatic colorectal cancer: a case-control study

Abstract

Background: Cancer patients (pts) are at increased risk of venous thrombotic events (VTE) which are associated with both increased morbidity and mortality. Tissue factor (TF) is the primary initiator of blood coagulation and preclinical data suggest that its expression is also controlled by KRAS. TF overexpression in cancer cells seems to be associated with KRAS mutation; the latter therefore might be a plausible link to hypercoagulability and increased VTE risk for metastatic colorectal cancer (mCRC) pts. Current guidelines do not recommend routine pharmacological VTE prophylaxis for such pts. Identifying novel predictors of VTE risk, based on the tumour molecular profile, would allow detecting pts more likely to benefit from thromboprophylaxis. Material(s) and Method(s): A retrospective case-control study was conducted. Cases had VTE (deep vein thrombosis (DVT), pulmonary embolism (PE), and/or migratory superficial thrombophlebitis) occurring within six months of the diagnosis of metastatic disease or to any time thereafter. Controls were pts with mCRC without VTE, matched for age, sex, year of diagnosis of metastatic disease, and presence of a central venous access device. Cases and controls were identified from the electronic health records of the Department of Oncology, Udine, and of the Department of Oncology, Pisa. Formalin-fixed, paraffin-embedded samples were reviewed and tested by pyrosequencing for KRAS status (codons 12, 13, 61 and 146). Nonmetastatic cases or those with indeterminate KRAS results, were excluded. Estimating that about 40% of mCRC harbor a KRAS mutation and with a cases/controls ratio of 1:2, the sample size needed to determine a significant odds ratio (OR) of 2.5 was approximately 77 cases and 154 controls, with a = 0.05 and a power of 80%. Logistic regression was used to determine whether there was an association between KRAS mutational status and VTE occurrence. Result(s): Between Jan 2008 and Dec 2014 a total of 68 cases with VTE and 177 controls without VTE were included. Thirty-four of the cases had DVT, 34 had PE. Of note, 6 patients had both thrombotic events. When VTE occurred, 37% of pts were receiving a bevacizumab-containing regimen. Among the controls, 38% received bevacizumab. Fifty-three (78%) of the cases and 137 (77%) of the controls had a central venous access device. In our analysis, KRAS mutated status (codon 12, 13, 61 and 146) was not associated with a higher risk of thrombosis with an OR of 1.34 (95% CI 0.77-2.36, p = 0.303) for VTE. Conclusion(s): Despite the trend towards an increased risk of VTE for pts with KRAS-mutant mCRC, our results were not statistically significant. Further studies are needed to investigate the link between KRAS mutation, TF overexpression and and VTE.